From nature to the laboratory and into the clinic

Abstract

Natural products possess a broad diversity of structure and function, and they provide inspiration for chemistry, biology, and medicine. In this review article, we highlight and place in context our laboratory's total syntheses of, and related studies on, complex secondary metabolites that were clinically important drugs, or have since been developed into useful medicines, namely amphotericin B (1), calicheamicin gamma(1)(I) (2), rapamycin (3), Taxol (4), the epothilones [e.g., epothilones A (5) and B (6)], and vancomycin (7). We also briefly highlight our research with other selected inspirational natural products possessing interesting biological activities [i.e., dynemicin A (8), uncialamycin (9), eleutherobin (10), sarcodictyin A (11), azaspiracid-1 (12), thiostrepton (13), abyssomicin C (14), platensimycin (15), platencin (16), and palmerolide A (17)].

Figure 1

Molecular structures of selected natural product drugs and drug leads.

Figure 2

Molecular structures of selected bioactive natural products.

Figure 3

Molecular structures of amphoteronolide B (18) and amphotericin B (1).

Figure 4

Molecular structures of calicheamicin γ₁^I (2) and gemtuzumab ozogamicin (Mylotarg®, 21).

Figure 5

Molecular structures of rapamycin (Rapamune®, 3) and temsirolimus (Torisel®, 35).

Figure 6

Molecular structures of paclitaxel (Taxol®, 4), docetaxel (Taxotere®, 38), and 10-deacetylbaccatin III (39).

Figure 7

Molecular structures of epothilones A (5) and B (6) and of ixabepilone (Ixempra®, 53).

Figure 8

Molecular structures of selected highly potent epothilone analogs (Nicolaou et al., 1998-2006).,

Figure 9

Molecular structures of vancomycin (7) and teicoplanin A₂-2 (65).

Figure 10

Molecular structure of a highly potent dimeric vancomycin analog active against vancomycin-resistant bacteria (Nicolaou et al., 2001).

Figure 11

Molecular structures of selected natural and designed enediyne compounds (Nicolaou et al., 1990-1992; 2007-2008).,,

Figure 12

Molecular structures of eleutherobin (10) and related compounds (Nicolaou et al., 1997-1998).,

Figure 13

Originally proposed (82) and corrected (12) molecular structures of azaspiracid-1 (Nicolaou et al., 2003-2004).,

Figure 14

Molecular structures of thiostrepton (13) and a simplified bioactive analog (83) (Nicolaou et al., 2004-2005).,

Figure 15

Molecular structures of platensimycin (15), platencin (16), and designed platensimycin analogs (Nicolaou et al., 2007-2008).,,-

Figure 16

Originally proposed (89) and revised (17) molecular structures of palmerolide A (Nicolaou, Chen et al., 2007).

Scheme 1

Application of the ketophosphonate-aldehyde macrocyclization to the total synthesis of amphoteronolide B (18) and amphotericin B (1) (Nicolaou et al., 1987).

Scheme 2

a) Application of the Ramberg-Bäcklund reaction to the preparation of simple enediyne model systems. b) Calculated cd distances (Nicolaou et al., 1988-1992).

Scheme 3

Highlights of the synthesis of the calicheamicin γ₁^I oligosaccharide domain (30) (Nicolaou et al., 1990).

Scheme 4

Highlights of the total synthesis of the calicheamicinone core and the total synthesis of calicheamicin γ₁^I (2) (Nicolaou et al., 1992).

Scheme 5

Application of the “double stitching” macrocyclization to the total synthesis of rapamycin (3) (Nicolaou et al., 1993).

Scheme 6

Diels-Alder based construction of the A-ring fragment of Taxol® (Nicolaou et al., 1994).

Scheme 7

Boron-tethered Diels-Alder based construction of the C-ring fragment of Taxol® (Nicolaou et al., 1994).

Scheme 8

Highlights of the total synthesis of Taxol® (4) (Nicolaou et al., 1994).

Scheme 9

Application of the olefin metathesis macrocyclization to the total synthesis of epothilone A (5) (Nicolaou et al., 1997).

Scheme 10

General one-step synthesis of epothilone analogs with various heteroaromatic ring systems (Nicolaou et al., 2002).

Scheme 11

Application of an atropselective Suzuki cross-coupling to the construction of triazine 70 (Nicolaou et al., 1998).

Scheme 12

Application of the triazine-driven bisaryl ether synthesis to the total synthesis of vancomycin aglycon and vancomycin (7) (Nicolaou et al., 1998-1999).,

Scheme 13

Highlights of selected reactions of the abyssomicins (Nicolaou and Harrison, 2006-2007).